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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0687
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 9 3369-3373
Copyright © 2007 by The Endocrine Society

CLINICAL CASE SEMINAR

Hyperphagia and Early-Onset Obesity due to a Novel Homozygous Missense Mutation in Prohormone Convertase 1/3

I. Sadaf Farooqi, Karolien Volders, Richard Stanhope, Robert Heuschkel, Anne White, Emma Lank, Julia Keogh, Stephen O’Rahilly and John W. M. Creemers

University Department of Clinical Biochemistry (I.S.F., E.L., J.K., S.O.), Addenbrooke’s Hospital, Cambridge CB2 2XY, United Kingdom; Department for Human Genetics (K.V., J.W.M.C.), University of Leuven and Flanders Interuniversity Institute for Biotechnology, B-3000 Leuven, Belgium; Department of Endocrinology (R.S.), Great Ormond Street Hospital, London WC1N 3JH, United Kingdom; Department of Paediatric Gastroenterology (R.H.), Royal Free Hospital, London NW3 5NU, United Kingdom; and Endocrine Sciences (A.W.), Faculty of Life Sciences and Medical and Human Sciences, University of Manchester, Manchester M13 9PT, United Kingdom

Address all correspondence and requests for reprints to: Stephen O’Rahilly, University Department of Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge CB2 2XY, United Kingdom. E-mail: so104{at}medschl.cam.ac.uk.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Context: Congenital deficiency of the neuroendocrine-specific enzyme prohormone convertase (PC) 1/3 leads to a syndrome characterized by obesity, small intestinal dysfunction, and dysregulation of glucose homeostasis in humans. To date, only two unrelated subjects with this disorder have been reported.

Research Design and Methods: We now report a third proband, a 6-yr-old boy, offspring of a consanguineous union of parents of North African origin, who was homozygous for a novel missense mutation Ser307Leu. We characterized the functional properties of the mutant PC1/3 and characterized the clinical phenotype of the patient.

Results: In vitro this mutation markedly impairs the catalytic activity of the convertase. However, in contrast to other previously described naturally occurring mutations, intracellular trafficking of this mutant enzyme appeared normal. The Ser307Leu mutant retained some autocatalytic activity, even though it was completely inactive on other substrates. As with the previous two patients, this child had obesity and persistent diarrhea, however, there was no history of reactive hypoglycemia. The patient showed markedly increased food intake at an ad libitum test meal, confirming that hyperphagia makes a major contribution to the obesity seen in this syndrome.

Conclusion: This case extends the clinical and molecular spectrum of human congenital PC1/3 deficiency.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
MANY BIOLOGICALLY INACTIVE prohormones and neuropeptides are cleaved by prohormone convertases (PCs) to release biologically active peptides. PCs are a seven-member family of subtilisin-like serine endoproteases, of which PC1/3 and PC2 are expressed in neuroendocrine tissues (1). PC1/3 acts upon a range of substrates, including proinsulin, proglucagon, and proopiomelanocortin (POMC). PC1/3 is itself synthesized as an inactive precursor (proPC1/3), then undergoes several autocatalytic maturation events, first within the endoplasmic reticulum (ER) and then within the trans-Golgi network and secretory vesicles of the regulated secretory pathway to generate fully active enzyme that is stored in mature secretory granules (2).

We have previously reported two patients from unrelated United Kingdom Caucasian families who were compound heterozygous for mutations in the gene encoding PC1/3 (Fig. 1Go) (3, 4). The first patient was heterozygous for a missense mutation, Gly593Arg, which causes failure of propeptide cleavage of PC1/3 and its retention in the ER, and was also heterozygous for +4A>C in the splice donor site of intron 5, resulting in exon skipping, a frameshift, and the introduction of a premature stop codon in the catalytic domain (3). The second patient was compound heterozygous for a nonsense mutation, Glu250stop, which truncates the protein in the catalytic domain and an in-frame deletion, Ala213del (4). We showed that both mutations result in impaired function in vitro. We have previously reported that PC1/3 deficiency is characterized by a neonatal onset enteropathy, reactive hypoglycemia, early-onset obesity, and impaired prohormone processing (4).


Figure 1
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  		FIG. 1. Structure of PC1/3 and location of mutations identified to date. Proband 1 was found to be a compound heterozygote for G593R and A->C+4 in the splice donor site of intron 5, resulting in exon skipping, a frameshift, and premature stop codon in the catalytic domain. Proband 2 was a compound heterozygote for Glu250stop, which truncates the protein in the catalytic domain and Ala213del. Proband 3, reported here and outlined, was homozygous for S307L.

 
We now report a patient who was referred for the investigation of severe early-onset obesity and was found to have the classical clinical and biochemical features of PC1/3 deficiency. We went on to show that the proband was homozygous for a novel PC1/3 mutation, Ser307Leu that results in impaired autocatalytic activity. We also undertook detailed phenotypical studies to investigate energy intake and expenditure as contributory factors to the obesity in this patient.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
PCR and sequencing (see supplemental appendix, which is published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org)

Definitions of overweight and obesity. We used United Kingdom population-derived reference data for the calculation of body mass index SD scores (5).

Construction of vectors expressing mutant PC1/3 and PC1/3 maturation and activity (see supplemental appendix, which is published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org)

Clinical phenotyping. The clinical studies were performed after approval by the local regional ethics committee of Cambridge. All clinical studies were conducted in accordance with the principles of the Declaration of Helsinki and performed as previously described (6). ACTH precursors and ACTH were measured using ELISA formats of two-antibody immunometric assays, as previously described (7, 8). Insulin and proinsulin were measured as previously described (9).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The male proband was born at 39-wk gestation, the fifth child of consanguineous parents of Libyan origin. Watery diarrhea started on the eighth postnatal day, and persisted despite oral feeding with a variety of whole protein, hydrolysate, and amino acid-based infant formula feeds with differing contents of carbohydrate, including lactose, glucose polymer, glucose, and fructose, and fat (predominantly long-chain triglyceride and medium-chain triglyceride). He required 5-wk parenteral nutrition while establishing him on a hydrolyzed feed. He then gained weight with more formed stools on 120 kcal/kg of a formulated modular feed consisting of comminuted chicken feed, 5% glucose, 2% fructose, 3% medium-chain triglyceride, and 8 g metabolic mineral. Diarrhea improved, although normal stools were not achieved, even when the patient was fed nutritionally inadequate fat-free glucose- and amino acid-based formula feeds. Investigations confirmed malabsorption of monosaccharides and fat. Exocrine pancreatic function was preserved as indicated by a normal fecal elastase and no improvement on a therapeutic trial of pancreatic enzyme supplements. Duodenal biopsy at 4 months of age showed a focal increase in intraepithelial lymphocytes, with villous shortening, edema, irregularity, and vacuolation of the surface epithelium suggesting an enteropathy. Antienterocyte antibodies were absent. At the age of 4 yr, he developed polyuria and polydipsia. Although suggestive of diabetes insipidus, serum osmolality was not elevated (288 mmol/liter; normal range 282–300), and a water deprivation test was nondiagnostic.

At the age of 6 yr, the proband was referred for the further investigation of his severe obesity. Serum leptin was appropriate for the degree of obesity (35 ng/ml), excluding congenital leptin deficiency. However, fasting plasma concentrations of proinsulin (1079 pmol/liter, normal <7) and des-64,65 proinsulin (71 pmol/liter, normally undetectable) were very high, with levels of insulin (14 pmol/liter, normal <60) and des-31,32 proinsulin (25 pmol/liter, normal <16) that were inappropriately low; fasting blood glucose was 4.0 mmol/liter. In view of the combination of obesity and a highly abnormal insulin to proinsulin ratio, a clinical diagnosis of probable PC1/3 deficiency was made.

Direct sequencing of the PC1/3 gene revealed the child to be homozygous for a novel missense mutation, Ser307Leu (Fig. 1Go), which was not found in 100 control alleles from subjects of Arab origin. Both parents were heterozygous for the Ser307Leu missense mutation and were not obese. The proband was also homozygous for two common polymorphisms (Q665E and S690T) that have previously been reported and that did not impair PC1/3 function in vitro (data not shown).

We went on to characterize the functional consequences of the Ser307Leu mutation on PC1/3 activity and processing. Wild-type PC1/3 is synthesized as inactive proPC1/3 with a molecular mass of 94 kDa, which is rapidly converted into 87 kDa PC1/3 by autocatalytic cleavage of the amino-terminal propeptide in the ER (4, 10). To become fully activated, PC1 requires a second internal cleavage of the propeptide in a post-ER compartment (11). Further maturation of PC1/3 includes carboxyterminal processing, resulting in heterogeneous protein bands between 74 and 66 kDa (12). We first characterized the consequences of the Ser307Leu mutation on maturation and secretion by Western blotting (Fig. 2AGo). The mutation resulted in reduced propeptide cleavage, carboxyterminal processing, and secretion compared with wild-type PC1/3, in both HEK293T and ßTC3 cells. However, significant amounts of apparently mature PC1/3 were secreted, indicating that Ser307Leu is folded correctly. Subsequently, internal cleavage of the propeptide was investigated by coimmunoprecipitation experiments (Fig. 2BGo) (4). Immunoprecipitation of wild-type PC1/3 resulted in the coimmunoprecipitation of the intact propeptide (94 kDa) and the carboxyterminal fragment of the internally cleaved propeptide (3 kDa). Processing of substrates in trans (i.e. substrates other than PC1) was studied (Fig. 2CGo). This substrate is readily cleaved by wild-type PC1/3, but Ser307Leu did not show any activity above background, despite equal levels of expression.


Figure 2
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  		FIG. 2. Functional characterization of the Ser307Leu mutation. A, Western blot of cell lysates and medium of transfected HEK293 and ßTC3 cells using FLAG M2 for detection of recombinant PC1/3 proteins. B, Coimmunoprecipitation of the propeptide with PC1/3 from lysates of metabolically labeled HEK293 cells. FLAG M1 was used for immunoprecipitation. The lower panel was exposed longer to obtain similar densities of the bands. C, Activity of recombinant PC1/3 immunopurified from transfected HEK293 cells using the fluorogenic substrate p-Glu-Arg-Thr-Arg-Arg-amino methylcoumarin. Similar expression levels of wild type (WT) and Ser307Leu were confirmed by Western blot (inset). {Delta}CT, Carboxyterminally truncated PC1/3.

 
We then studied the metabolic phenotype associated with PC1/3 deficiency. The proband developed obesity in the second year of life, deviating from predicted centiles for weight (Fig. 3AGo). He was reported to be hyperphagic, exhibiting food-seeking behavior in the free-living situation. We undertook an 18-MJ ad libitum test meal after an overnight fast and observed an increased ad libitum energy intake compared with normal weight subjects of the same age (Fig. 3BGo). The degree of hyperphagia was comparable to that reported by us previously in patients with heterozygous mutations in the melanocortin 4 receptor gene (6). Basal metabolic rate measured by indirect calorimetry after an overnight fast (7.3 MJ/d) was comparable to that predicted by age and gender-specific equations (6.8 MJ/d). In view of the impaired prohormone processing and neuroendocrine dysfunction seen in the other two patients with PC1/3 deficiency, we undertook further endocrine evaluation. We observed a low 0900 serum cortisol (78 nmol/liter, normal range 200–500) and, therefore, measured ACTH precursors using a specific ELISA, which required binding of antibodies to both the ACTH and {gamma}-MSH regions of POMC. The levels of ACTH precursors were markedly elevated (549 pmol/iter, normal <50), consistent with a degree of impaired POMC processing, whereas plasma ACTH concentrations were within the normal range (49 ng/liter, normal range 5–50). We observed an elevated TSH (4.8 pmol/liter, normal range 0.4–4.0) with a free T4 concentration at the lower end of the normal range (10.2 pmol/liter, normal range 9–21), which is consistent with hypothalamic hypothyroidism. The patient was given hydrocortisone and T4 supplementation.


Figure 3
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  		FIG. 3. A, Weight gain in patient with PC1/3 mutation compared with normal centiles for boys. B, Increased food intake at an ad libitum test meal compared with patients with leptin deficiency and heterozygous for complete loss of function mutations in the melanocortin 4 receptor gene.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In 1997, we provided the first description of humans with mutations in the PC1/3 gene (3). This child represents the third reported case of human PC1/3 deficiency, being homozygous for a loss of function mutation (Ser307Leu), which results in reduced maturation and secretion of PC1/3, although retention in the ER was not observed in immunofluorescence studies (data not shown). Ser307 is located two amino acids amino-terminal of the oxyanion hole Asn and is conserved in all proprotein convertases (13). Based on the crystal structure of furin (14), it is predicted that Ser307 is not directed at the substrate and does, therefore, not directly interfere with substrate binding (15). Although the larger side-chain of leucine compared with serine might be accommodated, the pocket is surrounded by hydrophilic residues (Ser318, Thr367, and Glu331 in furin) and backbone oxygen atoms, and, as such, insertion of the hydrophobic side chain of Leu is likely to destabilize the structure near the oxyanion hole. Analysis of the internal propeptide cleavage of Ser307Leu revealed severe impairment in this activation step. The exact position of internal cleavage of the propeptide of PC1/3 has not been determined, but it has been suggested to be either carboxyterminal of His-Pro-Arg-Arg78 (15) or His-Pro-Arg-Arg-Ser-Arg-Arg81 (16). The observed doublet of approximately 3 kDa might represent both cleavages.

This child presented with neonatal onset enteropathy for which no specific cause was identified. Diarrhea in early infancy was associated with a generalized malabsorptive picture involving simple nutrients, such as monosaccharides and amino acids, suggestive of a nonselective decline in the capacity to absorb nutrients. Enteroendocrine cells and their products play an important role in the capacity of the small intestine to absorb simple nutrients and intestinal motility, as seen in recently described patients with mutations in neurogenin-3, who had a comparable gastrointestinal phenotype (17). PC1/3 deficiency should be considered in patients presenting with intractable neonatal onset diarrhea, in whom other causes have been excluded.

Because GLP-2 is coproduced with GLP-1 at a 1:1 M ratio in intestinal L cells (18), it is plausible that the enteropathy associated with PC1/3 deficiency is in part attributable to the impaired processing and secretion of GLP-2 from the gut mucosa, the principal action of which is to stimulate the proliferation and repair of the intestinal epithelium. It is conceivable that these patients might benefit from therapy with GLP-2, which may ameliorate the severity of the enteropathy (18).

Consistent with the previously reported children, this child also had severe hyperphagia and obesity. Birth weights have been unremarkable in all children reported to date, including our patient, indicating that the effects on growth and weight are postnatal. For the first time, we had an opportunity to measure directly energy intake and expenditure in this syndrome. The patient was objectively hyperphagic at an ad libitum test meal, but energy expenditure was in the normal range. Linear growth was normal (height age 6 yr = 98 cm, 98th centile). PC1/3 has numerous substrates that are known to be involved in energy homeostasis, including POMC, Agouti related peptide, cholecystokinin, and glucagon-like peptide-1. However, it is particularly likely that disrupted POMC processing in the hypothalamus plays a role in the development of obesity, due to reduced melanocortin signaling in the hypothalamus. Although we have not directly assessed the impact of Ser307Leu on POMC processing in the hypothalamus, we have observed very high levels of unprocessed POMC in the circulation, indicating a general defect in the POMC processing cascade. Interestingly, ACTH levels in plasma were within the normal range, despite a complete lack of PC1/3 enzymatic activity. This phenomenon has been observed in other patients with mutations in PC1/3 (4) and indicates that biosynthesis of ACTH is not entirely dependent on PC1/3.

PC1/3 deficiency has been described in two independent mouse models with notable differences in phenotype. In one mouse model, about 40% of PC1/3 null embryos die before birth, and another 40% within 6 d (19). The remaining pups appear normal at birth but are only 60% the size of heterozygous or wild-type littermates, with reduced growth associated with decreased levels of GH mRNA and decreased circulating GH (19). They suffer from chronic mild diarrhea associated with bulky moist stools. Blood glucose levels are normal despite a severe impairment in proinsulin processing, which results in accumulation of immature secretory granules in the pancreatic ß-cells. However, these PC1/3 null mice were not reported to be obese, leading to the suggestion that PC1/3 may serve different functions in rodents compared with humans. Recently, a second mouse model of PC1/3 deficiency has been generated by chemical mutagenesis, resulting in a homozygous missense mutation (Asn222Asp) in the catalytic domain (20). These mice are hyperproinsulinemic and 30% heavier than wild-type littermates, with an increase in food intake as we have observed in humans. The Asn222Asp mutation in this mouse model reduces the cleavage of a fluorogenic substrate by approximately 50% (20). In in vitro studies of the Asn222Asp mutant, we also find an approximate 50% reduction in activity compared with wild-type PC1/3 (data not shown). In the same expression system, all five human mutant PC1/3 alleles do not display any activity on substrates in trans. However, it remains plausible that residual PC1/3 activity may be present in the patients in vivo.

In summary, we describe the third case of human PC1/3 deficiency in a patient presenting with severe early-onset obesity and a history of neonatal onset enteropathy. We have established that the gastrointestinal phenotype is a major feature of human PC1/3 deficiency, which is particularly important given that only one case has been previously described with this as a major presenting feature. We show for the first time that the obesity phenotype seen in PC1/3 deficiency is largely driven by an increase in food intake, consistent with impaired processing of neuropeptides involved in feeding behavior such as POMC. These studies further refine the phenotype of this rare but illuminating genetic disorder.


   Acknowledgments
 
We thank Sandra Meulemans for technical assistance and Roland Siezen and Bernadet Renckens (Radboud University Nijmegen) for structural analysis of the mutation. Rob Oliver undertook the analysis of adrenocorticotrophic hormone precursors and adrenocorticotrophic hormone.


   Footnotes
 
This work was supported by grants from the Wellcome Trust (to I.S.F. and S.O.) and the Medical Research Council (to S.O.).

Disclosure Statement: The authors have nothing to declare.

First Published Online June 26, 2007

Abbreviations: ER, Endoplasmic reticulum; PC1/3, prohormone convertase; POMC, proopiomelanocortin.

Received March 27, 2007.

Accepted June 19, 2007.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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